Could interleukin-15 potentiate histone deacetylase inhibitor effects in haematological malignancy?

Abstract

Despite significant progress in cancer therapy, prognosis in acute leukaemia remains dismal, and the development of new therapies is urgently warranted: in acute myeloid leukaemia, the current cure rate is of 30–40% in younger and much less in older patients.Chromatin remodeling through histone acetylation is one of the major mechanisms of transcriptional control of genes, and is involved in ‘gene silencing’ of antioncogenes in various tumour cells. Chromatin remodeling is also involved in transcriptional control of other genes, such as NKG2D ligand genes.Histone deacetylases and acetyltransferases are involved in the epigenetic regulation of gene expression, and increased/decreased activity of histone deacetylases has been reported in several cancer types. Histone deacetylase inhibitors were reportedly active in many cancers including hematological malignancies, and have been shown in numerous experiments to reduce cancer cell growth and enhance cell differentiation, growth arrest and apoptosis. In acute myeloid leukaemia, histone deacetylase inhibitors alone had limited efficacy, but their combination with other anticancer agents yielded promising results.Interleukin (IL)-15 is regarded with great hope in the immunotherapy of cancer, and IL-15-activated cytokine-induced killer cells showed potent antileukemic activity both in vitro and in vivo. IL-15 increases expression of NKG2D and its ligands and can increase natural killer cell mediated cytotoxicity against tumour cells. The administration of IL-15 was recently shown to be safe in preclinical models, and there are ongoing clinical trials of IL-15 in patients with cancer and HIV infection.We hypothesise that IL-15 will synergise with histone deacetylase inhibitors in increasing the levels of activatory NKG2D receptors on natural killer and CD8+ T cells and of their ligands, the MHC class I related molecule A and B, on tumor cells, and will enhance innate immune antitumour responses in acute myeloid leukaemia and other haematological malignancies. Up-regulation of NKG2D–NKG2D-ligand antitumour immune response by combining histone deacetylase inhibitors with IL-15 has the potential to improve the efficacy of acute myeloid leukaemia treatment.